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Hemodynamic measurements such as cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) can provide useful information for the diagnosis and characterization of brain tumors. Previous work showed that arterial spin labeling (ASL) in combination with vasoactive stimulation enabled simultaneous non-invasive evaluation of both parameters, however this approach had not been previously tested in tumors. The aim of this work was to investigate the application of this technique, using a pseudo-continuous ASL (PCASL) sequence combined with breath-holding at 3 T, to measure CBF and CVR in high-grade gliomas and metastatic lesions, and to explore differences across tumoral-peritumoral regions and tumor types. To that end, 27 patients with brain tumor were studied. Baseline CBF and CVR were measured in tumor, edema, and gray matter (GM) volumes-of-interest (VOIs). Peritumoral ipsilateral ring-shaped VOIs were also generated and mirrored to the contralateral hemisphere. Differences in baseline CBF and CVR were evaluated between contralateral and ipsilateral GM, contralateral and ipsilateral peritumoral rings, and among VOIs and tumor types. CBF in the tumor was higher in grade 4 gliomas than metastases. In grade 4 gliomas, edema had lower CBF than the tumor and contralateral GM. CVR values were different between grade 3 and grade 4 gliomas, and between grade 4 and metastases. CVR values in the tumor were lower compared to the contralateral GM. Differences in CVR between contralateral and ipsilateral-ring VOIs were also found in grade 4 gliomas, presumably suggesting tumor infiltration within the peritumoral tissue. A cut-off value for CVR of 27.9%-signal-change is suggested to differentiate between grade 3 and grade 4 gliomas (specificity = 83.3%, sensitivity = 70.6%). In conclusion, CBF and CVR mapping with ASL offered insights into the perilesional environment that could help to detect infiltrative disease, particularly in grade 4 gliomas. CVR emerged as a potential biomarker to differentiate between grade 3 and grade 4 gliomas., (© 2025 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Reliable language mappings require sufficient language skills. This study evaluated whether linguistic task properties impact feasibility and reliability of navigated transcranial magnetic stimulation (nTMS)-based language mappings in aphasic glioma patients., Methods: The effect of linguistic complexity on naming accuracy during baseline testing without stimulation and on the number of errors during nTMS was evaluated for 16 moderately and 4 severely expressive aphasic patients., Result: During baseline, items acquired later in life and used less frequently, a higher amount of multisyllabic, compound, and inanimate items were named inaccurately. Even after removing these more complex items, less frequent and multisyllabic items were more error-prone during stimulation., Conclusion: Higher linguistic item complexity was associated with decreased naming accuracy during baseline and resulted in a potentially higher false positive rate during nTMS in aphasic glioma patients. Thus, tailoring task complexity to individual performance capabilities may considerably support the preservation of residual functionality., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This trial was funded entirely by institutional grants from the Department of Neurosurgery, Technical University of Munich, Germany, School of Medicine, Klinikum rechts der Isar. Sebastian Ille, Sandro M. Krieg, and Bernhard Meyer are consultants for Brainlab AG. Sebastian Ille is also a consultant for Icotec AG and Carl Zeiss Meditec AG and has past honoraria from Nexstim AG. Sandro M. Krieg is a consultant for Ulrich Medical and Need Inc. and received honoraria from Nexstim Plc, Spineart Deutschland GmbH, Medtronic, and Carl Zeiss Meditec AG. Bernhard Meyer received honoraria, consulting fees, and research grants from Medtronic, Icotec AG, and Relievant Medsystems Inc., honoraria and research grants from Ulrich Medical, honoraria and consulting fees from Spineart Deutschland GmbH and DePuy Synthes, royalties from Spineart Deutschland GmbH, and has a financial relationship with Medacta. The other authors have no personal, financial, or institutional interest in any drugs, materials, or devices described in this article. All authors declare that they have no conflict of interest regarding the materials used as well as the results presented in this study., (Copyright © 2025. Published by Elsevier Inc.)

High gamma activity (HGA) is a crucial biomarker for functional brain mapping, particularly in sensorimotor areas, to preserve functionality after brain surgeries. HGA mapping paradigms typically involve multiple task blocks alternating with resting (R) conditions, where each block comprises consecutive tasks under nonresting (NR) conditions. However, the repetitive nature of these tasks may lead to attenuation due to repetition suppression, potentially compromising the accuracy of HGA mapping. This study tests the hypothesis that repetitive grasping paradigms result in attenuated HGA over time in sensorimotor areas. It explores the temporal and spatial characteristics of this attenuation to optimize electrocorticography (ECoG) HGA protocols and enhance result interpretation. Eleven consecutive patients who underwent surgical treatment of intractable epilepsy or malignant glioma were included in this study. Intracranial electrode locations on the pre- and postcentral gyrus were considered regions of interest (ROI). Each patient performed ten blocks of ten consecutive grasping trials. The mean z-scored HGA (60-170 Hz) across these trials was calculated, and attenuation was analyzed using the Kruskal-Wallis test. Obtained signals were also divided into three grouped periods for R and NR groups to assess short-term attenuation within movement blocks and long-term attenuation over multiple blocks. Electrode locations were mapped to the MNI152 (Montreal Neurological Institute) brain template to investigate the spatial distribution of attenuation. Distances from each electrode to the hand-knob region were compared between attenuated and nonattenuated electrodes. A total of 568 electrodes from 11 patients were analyzed, including 139 electrodes within the ROI. Thus, 60 electrodes demonstrated significant HGAs during the grasping task (p < 0.05). Sensorimotor HGA z-scores significantly attenuated over time during both consecutive grasping trials and repeated blocks. Short-term attenuation (25%, 15/60 electrodes in ROI) was more pronounced than long-term attenuation (15%, 9/60 electrodes in ROI). Notably, three patients undergoing intraoperative mapping demonstrated less short-term attenuation compared to long-term attenuation. Spatially, attenuated electrodes clustered around the hand-knob region of the precentral gyrus and adjacent areas of the postcentral gyrus. However, no significant differences were observed in the distances from electrodes to the hand-knob region between attenuated and nonattenuated electrodes. The present study showed that repetitive grasping tasks attenuated the HGA of significant electrodes in the sensorimotor area over time. Considering the findings with the characteristics can further improve the usability of ECoG mapping in terms of more precise results in the most reasonable mapping time., (© 2025 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

An endogenous time-keeping system found in all kingdoms of life, the endogenous circadian clock, is the source of the essential cyclic change mechanism known as the circadian rhythm. The primary circadian clock that synchronizes peripheral circadian clocks to the proper phase is housed in the anterior hypothalamus's suprachiasmatic nuclei (SCN), which functions as a central pacemaker. According to many epidemiological studies, many cancer types, especially brain tumors, have shown evidence of dysregulated clock gene expression, and the connection between clock and brain tumors is highly specific. In some studies, it is reported that the treatment administered in the morning has been linked to prolonged survival for brain cancer patients, and drug sensitivity and gene expression in gliomas follow daily rhythms. These results suggest a relationship between the circadian rhythm and the onset and spread of brain tumors, while further accumulation of research evidence will be needed to establish definitely these positive outcomes as well as to determine the mechanism underlying them. Chronotherapy provides a means of harnessing current medicines to prolong patients' lifespans and improve their quality of life, indicating the significance of circadian rhythm in enhancing the design of future patient care and clinical trials. Moreover, it is implicated that chronobiological therapy target may provide a significant challenge that warrants extensive effort to achieve. This review examines evidence of the relationship of circadian rhythm with glioma molecular pathogenesis and summarizes the mechanisms and drugs implicated in this disease., Competing Interests: Declaration of competing interest No potential conflicts of interest were reported by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neuroplasticity is well established in low grade glioma patients. Less is known about functional plasticity in glioblastomas. A 56-year-old lady presented with a recurrent speech deficit seventeen months after her initial craniotomy for a language eloquent glioblastoma (GBM). Pre-operative navigated trans-cranial magnetic stimulation (n-TMS) for language mapping, tractography and intra-operative language mapping were performed. During her second admission, preoperative n-TMS revealed positive responses anterior and posterior to the tumour recurrence. Tractography revealed a decrease in the anterior extension of the Arcuate Fasciculus (AF) in the inferior frontal gyrus and a more anterior component of the Frontal-Aslant Tract (FAT) showed anterior to the tumour itself. A second resection was carried out and the patient was discharged with no language deficit for second line treatment with Lomustine. Intraoperatively, speech arrest was found in a new position posterior to the previous surgical cavity and away from tumour recurrence (where speech arrest was previously located). This case report shows language function neuroplasticity in glioblastoma. This is supported by preoperative cortical and subcortical mapping., Competing Interests: Declarations. Ethics approval: Not applicable. Consent to participate: Informed consent was obtained from the patient included in the study. Consent for publication: The patient has consented for the publication of this study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Gliomas are the most common malignant primary brain tumor and are often associated with severe neurological deficits and mortality. Unlike many cancers, gliomas rarely metastasize outside the brain, indicating a possible dependency on unique features of brain microenvironment. Synapses between neurons and glioma cells exist, suggesting that glioma cells rely on neuronal inputs and synaptic signaling for proliferation. Yet, the locations and properties of neurons that innervate gliomas have remained elusive. In this study, we utilized transsynaptic tracing with an EnvA-pseudotyped, glycoprotein-deleted rabies virus to specifically infect TVA and glycoprotein-expressing human glioblastoma cells in an orthotopic xenograft mouse model, allowing us to identify the neurons that form synapses onto the gliomas. Comprehensive whole-brain mapping revealed that these glioma-innervating neurons (GINs) from brain regions, including diverse neuromodulatory centers and specific cortical layers, known to project to the glioma locations. Molecular profiling revealed that long-range cortical GINs are predominantly glutamatergic, and subsets express both glutamatergic and GABAergic markers, whereas local striatal GINs are largely GABAergic. Electrophysiological studies demonstrate that while GINs share passive intrinsic properties with cortex-innervating neurons, their action potential waveforms are altered. Our study introduces a method for identifying and mapping GINs and reveals their consistent integration into existing location-dependent neuronal networks involving diverse neurotransmitters and neuromodulators. The observed intrinsic electrophysiological differences in GINs lay the groundwork for future investigations into how these alterations relate to the postsynaptic characteristics of glioma cells., Competing Interests: Competing interests statement:M.C.H. serves on the scientific advisory boards of Alixia, Minovia, and MitoQ and is on the editorial boards of Cell Metabolism and Molecular Cell. M.C.H. received research funding from Agilent Technologies and ReFuel Bio. M.C.H. is a consultant and founder of ReFuel Bio.

Research on the neural imprint of dual-language experience, crucial for understanding how the brain processes dominant and non-dominant languages, remains inconclusive. Conflicting evidence suggests either similarity or distinction in neural processing, with implications for bilingual patients with brain tumors. Preserving dual-language functions after surgery requires considering pre-diagnosis neuroplastic changes. Here, we combine univariate and multivariate fMRI methodologies to test a group of healthy Spanish-Basque bilinguals and a group of bilingual patients with gliomas affecting the language-dominant hemisphere while they overtly produced sentences in either their dominant or non-dominant language. Findings from healthy participants revealed the presence of a shared neural system for both languages, while also identifying regions with distinct language-dependent activation and lateralization patterns. Specifically, while the dominant language engaged a more left-lateralized network, speech production in the non-dominant language relied on the recruitment of a bilateral basal ganglia-thalamo-cortical circuit. Notably, based on language lateralization patterns, we were able to robustly decode (AUC: 0.80 ± 0.18) the language being used. Conversely, bilingual patients exhibited bilateral activation patterns for both languages. For the dominant language, regions such as the cerebellum, thalamus, and caudate acted in concert with the sparsely activated language-specific nodes. In the case of the non-dominant language, the recruitment of the default mode network was notably prominent. These results demonstrate the compensatory engagement of non-language-specific networks in the preservation of bilingual speech production, even in the face of pathological conditions. Overall, our findings underscore the pervasive impact of dual-language experience on brain functional (re)organization, both in health and disease., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Objectives: Precise mapping of functional networks in patients with brain tumor is essential for tailoring personalized treatment strategies. Resting-state functional MRI (rs-fMRI) offers an alternative to task-based fMRI, capable of capturing multiple networks within a single acquisition, without necessitating task engagement. This study demonstrates a strong concordance between preoperative rs-fMRI maps and the gold standard intraoperative direct electric stimulation (DES) mapping during awake surgery., Methods: We conducted an analysis involving 28 patients with glioma who underwent awake surgery with DES mapping. A total of 100 DES recordings were collected to map sensorimotor (SMN), language (LANG), visual (VIS), and speech articulation cognitive domains. Preoperative rs-fMRI maps were generated using an updated version of the ReStNeuMap software, specifically designed for rs-fMRI data preprocessing and automatic detection of 7 resting-state networks (SMN, LANG, VIS, speech articulation, default mode, frontoparietal, and visuospatial). To evaluate the agreement between these networks and those mapped with invasive cortical mapping, we computed patient-specific distances between them and intraoperative DES recordings., Results: Automatically detected preoperative functional networks exhibited excellent agreement with intraoperative DES recordings. When we spatially compared DES points with their corresponding networks, we found that SMN, VIS, and speech articulatory DES points fell within the corresponding network (median distance = 0 mm), whereas for LANG a median distance of 1.6 mm was reported., Conclusion: Our findings show the remarkable consistency between key functional networks mapped noninvasively using presurgical rs-fMRI and invasive cortical mapping. This evidence highlights the utility of rs-fMRI for personalized presurgical planning, particularly in scenarios where awake surgery with DES is not feasible to protect eloquent areas during tumor resection. We have made the updated tool for automated functional network estimation publicly available, facilitating broader utilization of rs-fMRI mapping in various clinical contexts, including presurgical planning, functional reorganization over follow-up periods, and informing future treatments such as radiotherapy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

Background: Perfusion magnetic resonance imaging (MRI)s plays a central role in the diagnosis and monitoring of neurovascular or neurooncological disease. However, conventional processing techniques are limited in their ability to capture relevant characteristics of the perfusion dynamics and suffer from a lack of standardization., Purpose: We propose a physics-informed deep learning framework which is capable of analyzing dynamic susceptibility contrast perfusion MRI data and recovering the dynamic tissue response with high accuracy., Methods: The framework uses physics-informed neural networks (PINNs) to learn the voxel-wise TRF, which represents the dynamic response of the local vascular network to the contrast agent bolus. The network output is stabilized by total variation and elastic net regularization. Parameter maps of normalized cerebral blood flow (nCBF) and volume (nCBV) are then calculated from the predicted residue functions. The results are validated using extensive comparisons to values derived by conventional Tikhonov-regularized singular value decomposition (TiSVD), in silico simulations and an in vivo dataset of perfusion MRI exams of patients with high-grade gliomas., Results: The simulation results demonstrate that PINN-derived residue functions show a high concordance with the true functions and that the calculated values of nCBF and nCBV converge towards the true values for higher contrast-to-noise ratios. In the in vivo dataset, we find high correlations between conventionally derived and PINN-predicted perfusion parameters (Pearson's rho for nCBF: 0.84 ± 0.03 $0.84 \pm 0.03$ and nCBV: 0.92 ± 0.03 $0.92 \pm 0.03$ ) and very high indices of image similarity (structural similarity index for nCBF: 0.91 ± 0.03 $0.91 \pm 0.03$ and for nCBV: 0.98 ± 0.00 $0.98 \pm 0.00$ )., Conclusions: PINNs can be used to analyze perfusion MRI data and stably recover the response functions of the local vasculature with high accuracy., (© 2024 American Association of Physicists in Medicine.)

Gliomas are the most common primary brain tumors, representing approximately 28% of all central nervous system tumors. These tumors are characterized by rapid progression and show a median survival of approximately 18 months. The therapeutic options consist of surgical resection followed by radiotherapy and chemotherapy. Despite the multidisciplinary approach and the biomolecular role of targeted therapies, the median progression-free survival is approximately 6-8 months. The incomplete tumor compliance with treatment is due to several factors such as the presence of the blood-brain barrier, the numerous pathways involved in tumor transformation, and the presence of intra-tumoral mutations. Among these, the interaction between the mutations of genes involved in tumor bio-energetic metabolism and the functional response of the tumor has become the protagonist of numerous studies. In this scenario, the main role is played by mitochondria, cellular organelles delimited by a double membrane and containing their own DNA (mtDNA), which participates in numerous cellular processes such as the regulation of cellular metabolism, cellular proliferation, and apoptosis and is also the main source of cellular energy production. Therefore, it is understood that the mitochondrion, specifically its functional alteration, is a leading figure in tumor transformation, including brain tumors. The acquisition of mutations in the mitochondrial DNA of tumor cells and the subsequent identification of the so-called mitochondria-related genes (MRGs), both functional (mutation of Complex I) and structural (mutations of Complex III/IV), have been seen to play an important role in metabolic reprogramming with increased proliferation, resistance to apoptosis, and the progression of tumorigenesis. This demonstrates that these mitochondrial alterations could have a role not only in the intrinsic tumor biology but also in the extrinsic one associated with the therapeutic response. We aim to summarize the main mitochondrial dysfunction interactions present in gliomas and how they might impact prognosis.

After resective glioma surgery in the Supplementary Motor Area (SMA), patients often experience a transient disturbance of the ability to initiate speech and voluntary motor actions, known as the SMA syndrome (SMAS). It has been proposed that enhanced interhemispheric functional connectivity (FC) within the sensorimotor system may serve as a potential mechanism for recovery, enabling the non-resected SMA to assume the function of the resected region. The purpose of the present study was to investigate the extent to which changes in FC can be observed in patients after resolution of the SMAS. Eight patients underwent resection of left SMA due to suspected gliomas, resulting in various levels of the SMA syndrome. Resting-state functional MR images were acquired prior to the surgery and after resolution of the syndrome. At the group level we found an increased connectivity between the unaffected (right) SMA and the primary motor cortex on the same side following surgery. However, no significant increase in interhemispheric connectivity was observed. These findings challenge the prevailing notion that increased interhemispheric FC serves as the only mechanism underlying recovery from SMA syndrome and suggest the presence of one or more alternative mechanisms., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Brain plasticity after multistep surgery in low-grade glioma is highly variable; the neurosurgical approach must be individualised and functional imaging can be used for this purpose. In supplementary motor area complex (SMAC) tumors, the early and adequate functional recovery of patients raises the possibility of a latent bihemispheric or "mirror" cortico-subcortical network, which would develop depending on the needs of each patient., Methods: Functional and DTI-MR data from 4 right-handed patients with left frontal low grade gliomas near the SMAC, who were operated at least in two occasions were collected. The time of the reintervention was variable (18 months- 8 years), related to the tumor growth. All patients were evaluated by a neuropsychologist and imaged before each surgery, in a 3 T MR, with a 24 multichanel head coil Motor and expressive language task-fMRI and DTI sequences were obtained to evidence the main cortico-subcortical components of the SMAC. Data were processed with Brainwave (GE Medical Systems) and with an Iplan Fiber Tracking tool (MEDTRONIC), respectively RESULTS: None of our patients presented permanent neurological deficits after the first or second functional surgery. Three patients with partial or complete resection of the left middle and / or inferior frontal gyrus, and the left frontal aslant tract evidenced new right hemispherical cortical activity. This right shift were not observed in the patient without left middle gyrus resection, indeed with partial absent of the left frontal aslant tract., Conclusion: SMAC is a latent cortico-subcortical bihemispheric network that allows it to reorganize itself in response to specific neurological deficits. We highlight the importance in the cortical reorganization of the left middle frontal gyrus in the SMAC, closely connected with the essential language areas of this region, but also we focused in the potential cortioco-subcortical changes to compensate the functionality of the FAT., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interest to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Supplementary motor area (SMA) syndrome commonly occurs after glioma resection and requires weeks to months of recovery., Methods: Thirty-four glioma patients with SMA syndrome were reviewed and assigned to recovered and non-recovered groups based on whether their motor function recovered on postoperative day 7. To validate the association between variations in nodal properties and recovery time, neuro-navigated repetitive transcranial magnetic stimulation (nrTMS) was applied to stimulate potential nodes. Nine other patients (five nrTMS therapy and four sham-nrTMS treatments) with SMA syndrome with unrecovered motor functions on postoperation day 7 were prospectively enrolled., Results: The potential nodes of the sensorimotor network related to recovery time were investigated using preoperative and postoperative resting-state functional magnetic resonance imaging, graph theoretical analysis, and dynamic functional connectome analysis. Nodal efficiency of the lesional-hemispheric upper limb region of BA 4 (A4ul&#95;L) increased in the recovered group (preoperative, 0.472 ± 0.027; postoperative, 0.535 ± 0.020; p = 0.0006). The patients in the nrTMS therapy group quickly recovered (12.0 ± 1.6 days) compared to the sham-nrTMS group (29.5 ± 3.8 days, p = 0.0024). Variations in A4ul&#95;L nodal efficiency was negatively correlated with recovery time (r = -0.841; p = 0.0046)., Conclusion: A4ul&#95;L demonstrates enhanced postoperative nodal efficiency and shows therapeutic potential in SMA syndrome recovery, suggesting its viability as a therapeutic target., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Mechanical stress and fluid flow influence glioma cell phenotype in vitro, but measuring these quantities in vivo continues to be challenging. The purpose of this study was to predict these quantities in vivo, thus providing insight into glioma physiology and potential mechanical biomarkers that may improve glioma detection, diagnosis, and treatment. Image-based finite element models of human U251N orthotopic glioma in athymic rats were developed to predict structural stress and interstitial flow in and around each animal's tumor. In addition to accounting for structural stress caused by tumor growth, our approach has the advantage of capturing fluid pressure-induced structural stress, which was informed by in vivo interstitial fluid pressure (IFP) measurements. Because gliomas and the brain are soft, elevated IFP contributed substantially to tumor structural stress, even inverting this stress from compressive to tensile in the most compliant cases. The combination of tumor growth and elevated IFP resulted in a concentration of structural stress near the tumor boundary where it has the greatest potential to influence cell proliferation and invasion. MRI-derived anatomical geometries and tissue property distributions resulted in heterogeneous interstitial fluid flow with local maxima near cerebrospinal fluid spaces, which may promote tumor invasion and hinder drug delivery. In addition, predicted structural stress and interstitial flow varied markedly between irradiated and radiation-naïve animals. Our modeling suggests that relative to tumors in stiffer tissues, gliomas experience unusual mechanical conditions with potentially important biological (e.g., proliferation and invasion) and clinical consequences (e.g., drug delivery and treatment monitoring)., (© 2024. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Background: Brain tumors are associated with impaired cognitive functioning, which may result from disruptions in brain structural connectivity. Estimating structural disconnections is a more advantageous representation of tumor impact and can be performed indirectly through normative brain atlases. Materials and Methods: Using a publicly available dataset of glioma and meningioma patient MRI scans and tumor masks, latent correlations were estimated between measures of structural disconnection and attention-based cognitive functioning. These measures included gray matter (GM) parcel damage, white matter tract damage, GM parcel-to-parcel disconnections, and reaction time (RTI) as part of the Cambridge Neuropsychological Test Automated Battery to assess attention. Results: Preprocessing pipelines with two different methods of minimizing the pathology impact on MRI normalization were utilized: cost-function masking and lesion filling. The results across both pipelines were nearly consistent, with significant correlations mainly found between RTI measures and the damage to the left inferior fronto-occipital and uncinate fasciculus, as well as the left prefrontal-visual disconnections. Conclusions: This alludes to the importance of left-hemispheric prefrontal-visual coupling in attention-based tasks, particularly those involving object- and feature-based attention.

Background and Purpose: Resting-state functional MRI (rs-fMRI) can be used to estimate functional connectivity (FC) between different brain regions, which may be of value for identifying cognitive impairment in patients with brain tumors. Unfortunately, neither rs-fMRI nor neurocognitive assessments are routinely assessed clinically, mostly due to limitations in examination time and cost. Since DSC perfusion MRI is often used clinically to assess tumor vascularity and similarly uses a gradient-echo-EPI sequence for T2*-sensitivity, we theorized a "pseudo-rs-fMRI" signal could be derived from DSC perfusion to simultaneously quantify FC and perfusion metrics, and these metrics can be used to estimate cognitive impairment in patients with brain tumors., Materials and Methods: Twenty-four consecutive patients with gliomas were enrolled in a prospective study that included DSC perfusion MRI, resting-sate functional MRI (rs-fMRI), and neurocognitive assessment. Voxelwise modeling of contrast bolus dynamics during DSC acquisition was performed and then subtracted from the original signal to generate a residual "pseudo-rs-fMRI" signal. Following the preprocessing of pseudo-rs-fMRI, full rs-fMRI, and a truncated version of the full rs-fMRI (first 100 timepoints) data, the default mode, motor, and language network maps were generated with atlas-based ROIs, Dice scores were calculated for the resting-state network maps from pseudo-rs-fMRI and truncated rs-fMRI using the full rs-fMRI maps as reference. Seed-to-voxel and ROI-to-ROI analyses were performed to assess FC differences between cognitively impaired and nonimpaired patients., Results: Dice scores for the group-level and patient-level (mean±SD) default mode, motor, and language network maps using pseudo-rs-fMRI were 0.905/0.689 ± 0.118 (group/patient), 0.973/0.730 ± 0.124, and 0.935/0.665 ± 0.142, respectively. There was no significant difference in Dice scores between pseudo-rs-fMRI and the truncated rs-fMRI default mode ( P = .97) or language networks ( P = .30), but there was a difference in motor networks ( P = .02). A multiple logistic regression classifier applied to ROI-to-ROI FC networks using pseudo-rs-fMRI could identify cognitively impaired patients (sensitivity = 84.6%, specificity = 63.6%, receiver operating characteristic area under the curve (AUC) = 0.7762 ± 0.0954 (standard error), P = .0221) and performance was not significantly different from full rs-fMRI predictions (AUC = 0.8881 ± 0.0733 (standard error), P = .0013, P = .29 compared with pseudo-rs-fMRI)., Conclusions: DSC perfusion MRI-derived pseudo-rs-fMRI data can be used to perform typical rs-fMRI FC analyses that may identify cognitive decline in patients with brain tumors while still simultaneously performing perfusion analyses., (© 2024 by American Journal of Neuroradiology.)

Introduction: Learning is a long-term memory process heavily influenced by the control processes implemented by working memory, including recognition of semantic properties of items by which subjects generate a semantic structure of engrams., Aim: The aim of this study is to investigate the verbal learning strategies of patients affected by a tumor in the left frontal lobe to highlight the role of area 9., Method: Ten patients with frontal low-grade gliomas and ten healthy control subjects, matched for age, sex and education, were recruited and then evaluated with a two-part verbal learning test: multi-trial word list learning in free recall, and multi-trial word list learning preceded by an explicit semantic strategy cue. Frontal patients were divided into two groups: those either with frontal lesions involving or sparing area 9., Results: In comparison to healthy control subjects, frontal patients with lesions involving area 9 memorized fewer words and displayed difficulty in using semantic strategies. When the strategy was suggested by the examiner, their performance improved, but to a lesser extent than the healthy control. Conversely, frontal patients with lesions sparing area 9 showed similar results to healthy control subjects., Conclusion: The results suggested that, while the identification of the categorical criterion requires the integrity of the entire dorsolateral prefrontal area, only area 9, and not the surrounding areas, could be responsible for the effective use of semantic strategies in learning tasks., (© 2024. The Author(s).)

Purpose: Motor evoked potential (MEP) monitoring has been widely applied in various neurosurgical operations. This study aimed to assess the predictive value of MEP monitoring for postoperative motor deficit (PMD) in patients with insular gliomas., Methods: Demographic and clinical data, MEP monitoring data, and follow-up data of 42 insular glioma patients were retrospectively reviewed, and 40 patients were finally enrolled. The value of MEP monitoring for predicting PMD was assessed with sensitivity, specificity, and false-positive/false-negative rates. Binary multivariate logistic regression analysis was performed to further identify the predictive value of MEP monitoring., Results: Statistical analysis showed that irreversible MEP changes, but not all MEP changes, were more effective in predicting PMD. The sensitivity and specificity of irreversible MEP changes for predicting long-term PMD were 85.71 and 93.94%, whereas the false-positive and -negative rates were 25.00 and 3.12% respectively. In addition, irreversible MEP changes were identified as the only independent predictor for long-term PMD (odds ratio, 101.714; 95% confidence interval, 6.001-1724.122; p = 0.001)., Conclusions: MEP monitoring has been proven to be feasible in insular glioma surgery. Irreversible MEP changes showed good performance in predicting PMD. Their absence can offer an optimistic expectation for the long-term motor outcome. The findings can provide the surgical team with a more effective interpretation of MEP changes and contribute to exploring tailored MEP warning criteria., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 by the American Clinical Neurophysiology Society.)

Although epilepsy is the most common comorbidity of brain tumors, epileptic spasms rarely occur. Brain tumors associated with epileptic spasms are mostly low-grade gliomas. To date, few studies in the literature have reported on malignant (Grades 3-4) brain tumors associated with epileptic spasms. Thus, we aimed to investigate the characteristics of malignant brain tumor-associated epileptic spasms. We retrospectively reviewed patients with malignant brain tumors and epileptic spasms in our institution. Data on demographics, tumor histology, magnetic resonance imaging, epileptic spasm characteristics, electroencephalography, and treatment responsiveness were also collected. Six patients were included. In all cases, the brain tumors occurred in infancy in the supratentorial region and epileptic spasm onset occurred after the completion of brain tumor treatment. Anti-seizure medication did not control epileptic spasms; two patients were seizure-free after epileptic surgery. Although all patients had developmental delays caused by malignant brain tumors and their treatment, developmental regression proceeded after epileptic spasm onset. Two patients who achieved seizure-free status showed improved developmental outcomes after cessation of epileptic spasms. This is the first report of the characteristics of malignant brain tumor-associated epileptic spasms. Our report highlights a difficulties of seizure control and possibillity of efficacy of epileptic surgery in this condition. In malignant brain tumor-associated epileptic spasms, it is important to proceed with presurgical evaluation from an early stage, bearing in mind that epileptic spasms may become drug-resistant., (© 2024 International League Against Epilepsy.)

Damage to the posterior language area (PLA), or Wernicke's area causes cortical reorganization in the corresponding regions of the contralateral hemisphere. However, the details of reorganization within the ipsilateral hemisphere are not fully understood. In this context, direct electrical stimulation during awake surgery can provide valuable opportunities to investigate neuromodulation of the human brain in vivo, which is difficult through the non-invasive approaches. Thus, in this study, we aimed to investigate the characteristics of the cortical reorganization of the PLA within the ipsilateral hemisphere. Sixty-two patients with left hemispheric gliomas were divided into groups depending on whether the lesion extended to the PLA. All patients underwent direct cortical stimulation with a picture-naming task. We further performed functional connectivity analyses using resting-state functional magnetic resonance imaging (MRI) in a subset of patients and calculated betweenness centrality, an index of the network importance of brain areas. During direct cortical stimulation, the regions showing positive (impaired) responses in the non-PLA group were localized mainly in the posterior superior temporal gyrus (pSTG), whereas those in the PLA group were widely distributed from the pSTG to the posterior supramarginal gyrus (pSMG). Notably, the percentage of positive responses in the pSMG was significantly higher in the PLA group (47%) than in the non-PLA group (8%). In network analyses of functional connectivity, the pSMG was identified as a hub region with high betweenness centrality in both the groups. These findings suggest that the language area can spread beyond the PLA to the pSMG, a hub region, in patients with lesion progression to the pSTG. The change in the pattern of the language area may be a compensatory mechanism to maintain efficient brain networks., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Purpose: Understanding the complex bidirectional interactions between neurons and glioma cells could help to identify new therapeutic targets. Herein, the techniques and application of novel neuroscience tools implemented to study the complex interactions between brain and malignant gliomas, their results, and the potential therapeutic opportunities were reviewed., Methods: Literature search was performed on PubMed between 2001 and 2023 using the keywords "glioma", "glioblastoma", "circuit remodeling", "plasticity", "neuron networks" and "cortical networks". Studies including grade 2 to 4 gliomas, diffuse midline gliomas, and diffuse intrinsic pontine gliomas were considered., Results: Glioma cells are connected through tumour microtubes and form a highly connected network within which pacemaker cells drive tumorigenesis. Unconnected cells have increased invasion capabilities. Glioma cells are also synaptically integrated within neural circuitry. Neurons promote tumour growth via paracrine and direct electrochemical mechanisms, including glutamatergic AMPA-receptors. Increased glutamate release in the tumor microenvironment and loss of peritumoral GABAergic inhibitory interneurons result in network hyperexcitability and secondary epilepsy. Functional imaging, local field potentials and subcortical mapping, performed in awake patients, have defined patterns of malignant circuit remodeling. Glioma-induced remodeling is frequent in language and even motor cortical networks, depending on tumour biological parameters, and influences functional outcomes., Conclusion: These data offer new insights into glioma tumorigenesis. Future work will be needed to understand how tumor intrinsic molecular drivers influence neuron-glioma interactions but also to integrate these results to design new therapeutic options for patients., (© 2024. The Author(s).)

Background: Non-invasive brain mapping using navigated transcranial magnetic stimulation (nTMS) is a valuable tool prior to resection of malignant brain tumors. With nTMS motor mapping, it is additionally possible to analyze the function of the motor system and to evaluate tumor-induced neuroplasticity. Distinct changes in motor cortex excitability induced by certain malignant brain tumors are a focal point of research., Methods: A retrospective single-center study was conducted involving patients with malignant brain tumors. Clinical data, resting motor threshold (rMT), and nTMS-based tractography were evaluated. The interhemispheric rMT-ratio (rMTTumor/rMTControl) was calculated for each extremity and considered pathological if it was >110% or <90%. Distances between the corticospinal tract and the tumor (lesion-to-tract-distance - LTD) were measured., Results: 49 patients were evaluated. 16 patients (32.7%) had a preoperative motor deficit. The cohort comprised 22 glioblastomas (44.9%), 5 gliomas of Classification of Tumors of the Central Nervous System (CNS WHO) grade 3 (10.2%), 6 gliomas of CNS WHO grade 2 (12.2%) and 16 cerebral metastases (32.7%). 26 (53.1%) had a pathological rMT-ratio for the upper extremity and 35 (71.4%) for the lower extremity. All patients with tumor-induced motor deficits had pathological interhemispheric rMT-ratios, and presence of tumor-induced motor deficits was associated with infiltration of the tumor to the nTMS-positive cortex ( p = 0.04) and shorter LTDs (all p < 0.021). Pathological interhemispheric rMT-ratio for the upper extremity was associated with cerebral metastases, but not with gliomas ( p = 0.002)., Conclusions: Our study underlines the diagnostic potential of nTMS motor mapping to go beyond surgical risk stratification. Pathological alterations in motor cortex excitability can be measured with nTMS mapping. Pathological cortical excitability was more frequent in cerebral metastases than in gliomas., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Background:  Resection of infiltrative neuroepithelial primary brain tumors, such as low-grade gliomas (LGGs) remains a neurosurgical challenge. Usual lack of clinical deficit despite LGGs growing in eloquent brain areas may be explained by reshaping and reorganization of functional networks. The development of modern diagnostic imaging techniques could disclose better understanding of the rearrangement of the brain cortex; however, mechanisms underlying such compensation and how it occurs in the motor cortex remain unclear. This systematic review aims to analyze the neuroplasticity of motor cortex in patients with LGGs, as determined by neuroimaging and functional techniques., Methods:  Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, medical subject headings (MeSH) and the following terms related to neuroimaging, LGGs and neuroplasticity were used with the Boolean operators AND and OR to synonymous terms in the PubMed database. Among the 118 results, 19 studies were included in the systematic review., Results:  Motor function in patients with LGG was characterized by a compensation in the contralateral and supplementary motor areas and premotor functional networks. Furthermore, ipsilateral activation in these types of gliomas was rarely described. Moreover, some studies did not reveal statistical significance in association between functional reorganization and the postoperative period, which can be explained by the low number of patients., Conclusion:  Our findings suggest a high pattern of reorganization per different eloquent motor areas and gliomas diagnosis. Understanding this process is useful to guide safe surgical resection and to develop protocols that assess the plasticity, even though functional network rearrangement needs to be better characterized by more studies., Competing Interests: None declared., (Thieme. All rights reserved.)

We retrospectively analyzed data from 15 patients, with a normal pre-operative cognitive performance, undergoing awake surgery for left fronto-temporal low-grade glioma. We combined a pre-surgical measure (fMRI maps of motor- and language-related centers) with intra-surgical measures (MNI-registered cortical sites data obtained during intra-operative direct electrical stimulation, DES, while they performed the two most common language tasks: number counting and picture naming). Selective DES effects along the precentral gyrus/inferior frontal gyrus (and/or the connected speech articulation network) were obtained. DES of the precentral gyrus evoked the motor speech arrest, i.e., anarthria (with apparent mentalis muscle movements). We calculated the number of shared voxels between the lip-tongue and overt counting related- and silent naming-related fMRI maps and the Volumes of Interest (VOIs) obtained by merging together the MNI sites at which a given speech disturbance was observed, normalized on their mean the values (i.e., Z score). Both tongue- and lips-related movements fMRI maps maximally overlapped (Z = 1.05 and Z = 0.94 for lips and tongue vs. 0.16 and -1.003 for counting and naming) with the motor speech arrest seed. DES of the inferior frontal gyrus, pars opercularis and the rolandic operculum induced speech arrest proper (without apparent mentalis muscle movements). This area maximally overlapped with overt counting-related fMRI map (Z = -0.11 and Z = 0.09 for lips and tongue vs. 0.9 and 0.0006 for counting and naming). Interestingly, our fMRI maps indicated reduced Broca's area activity during silent speech compared to overt speech. Lastly, DES of the inferior frontal gyrus, pars opercularis and triangularis evoked variations of the output, i.e., dysarthria, a motor speech disorder occurring when patients cannot control the muscles used to produce articulated sounds (phonemes). Silent object naming-related fMRI map maximally overlapped (Z = -0.93 and Z = -1.04 for lips and tongue vs. -1.07 and 0.99 for counting and naming) with this seed. Speech disturbances evoked by DES may be thought of as selective interferences with specific recruitment of left inferior frontal gyrus and precentral cortex which are differentiable in terms of the specific interference induced., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims: We intend to elucidate the alterations of cerebral networks in patients with insular glioma-related epilepsy (GRE) based on resting-state functional magnetic resonance images., Methods: We collected 62 insular glioma patients, who were subsequently categorized into glioma-related epilepsy (GRE) and glioma with no epilepsy (GnE) groups, and recruited 16 healthy individuals matched to the patient's age and gender to form the healthy control (HC) group. Graph theoretical analysis was applied to reveal differences in sensorimotor, default mode, visual, and executive networks among different subgroups., Results: No significant alterations in functional connectivity were found in either hemisphere insular glioma. Using graph theoretical analysis, differences were found in visual, sensorimotor, and default mode networks (p < 0.05). When the glioma located in the left hemisphere, the degree centrality was reduced in the GE group compared to the GnE group. When the glioma located in the right insula, the degree centrality, nodal efficiency, nodal local efficiency, and nodal clustering coefficient of the GE group were lower than those of the GnE group., Conclusion: The impact of insular glioma itself and GRE on the brain network is widespread. The networks altered by insular GRE differ depending on the hemisphere location. GRE reduces the nodal properties of brain networks than that in insular glioma., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

This study aims to investigate the structural reorganization in the sensorimotor area of the brain in patients with gliomas, distinguishing between those with impaired and unimpaired strength. Using voxel-based morphometry (VBM) and region of interest (ROI) analysis, gray matter volumes (GMV) were compared in the contralesional primary motor gyrus, primary sensory gyrus, premotor area, bilateral supplementary motor area, and medial Brodmann area 8 (BA8). The results revealed that in patients with right hemisphere gliomas, the right medial BA8 volume was significantly larger in the impaired group than in the unimpaired group, with both groups exceeding the volume in 16 healthy controls (HCs). In patients with left hemisphere gliomas, the right supplementary motor area (SMA) was more pronounced in the impaired group compared to the unimpaired group, and both groups were greater than HCs. Additionally, the volumes of the right medial BA8 in both the impaired group were greater than HCs. Contralateral expansions in the gray matter of hand- and trunk-related cortices of the premotor area, precentral gyrus, and postcentral gyrus were observed compared to HCs. Furthermore, a negative correlation was found between hand Medical Research Council (MRC) score and volumes of the contralateral SMA and bilateral medial BA8. Notably, our findings reveal consistent results across both analytical approaches in identifying significant structural reorganizations within the sensorimotor cortex. These consistent findings underscore the adaptive neuroplastic responses to glioma presence, highlighting potential areas of interest for further neurosurgical planning and rehabilitation strategies., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction: Functional magnetic resonance imaging is a powerful tool that has provided many insights into cognitive sciences. Yet, as its analysis is mostly based on the knowledge of an a priori canonical hemodynamic response function (HRF), its reliability in patients' applications has been questioned. There have been reports of neurovascular uncoupling in patients with glioma, but no specific description of the Hemodynamic Response Function (HRF) in glioma has been reported so far. The aim of this work is to describe the HRF in patients with glioma., Methods: Forty patients were included. MR images were acquired on a 1.5T scanner. Activated clusters were identified using a fuzzy general linear model; HRFs were adjusted with a double-gamma function. Analyses were undertaken considering the tumor grade, age, sex, tumor location, and activated location., Results: Differences are found in the occipital, limbic, insular, and sub-lobar areas, but not in the frontal, temporal, and parietal lobes. The presence of a glioma slows the time-to-peak and onset times by 5.2 and 3.8 % respectively; high-grade gliomas present 8.1 % smaller HRF widths than low-grade gliomas., Discussion and Conclusion: There is significant HRF variation due to the presence of glioma, but the magnitudes of the observed differences are small. Most processing pipelines should be robust enough for this magnitude of variation and little if any impact should be visible on functional maps. The differences that have been observed in the literature between functional mapping obtained with magnetic resonance vs. that obtained with direct electrostimulation during awake surgery are more probably due to the intrinsic difference in the mapping process: fMRI mapping detects all recruited areas while intra-surgical mapping indicates only the areas indispensable for the realization of a certain task. Surgical mapping might not be the gold standard to use when trying to validate the fMRI mapping process., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest with respect to the research, authorship and/or publication of this article., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Gliomas are primary brain tumours that are thought to develop from neural stem or progenitor cells that carry tumour-initiating genetic alterations. Based on microscopic appearance and molecular characteristics, they are classified according to the WHO classification of central nervous system (CNS) tumours and graded into CNS WHO grades 1-4 from a low to high grade of malignancy. Diffusely infiltrating gliomas in adults comprise three tumour types with distinct natural course of disease, response to treatment and outcome: isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas with the best prognosis; IDH-mutant astrocytomas with intermediate outcome; and IDH-wild-type glioblastomas with poor prognosis. Pilocytic astrocytoma is the most common glioma in children and is characterized by circumscribed growth, frequent BRAF alterations and favourable prognosis. Diffuse gliomas in children are divided into clinically indolent low-grade tumours and high-grade tumours with aggressive behaviour, with histone 3 K27-altered diffuse midline glioma being the leading cause of glioma-related death in children. Ependymal tumours are subdivided into biologically and prognostically distinct types on the basis of histology, molecular biomarkers and location. Although surgery, radiotherapy and alkylating agent chemotherapy are the mainstay of glioma treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways have improved outcome in subsets of patients., (© 2024. Springer Nature Limited.)

Objective: We investigated the feasibility of recording cortico-cortical evoked potentials (CCEPs) in patients with low- and high-grade glioma. We compared CCEPs during awake and asleep surgery, as well as those stimulated from the functional Broca area and recorded from the functional Wernicke area (BtW), and vice versa (WtB). We also analyzed CCEP properties according to tumor location, histopathology, and aphasia., Methods: We included 20 patients who underwent minimally invasive surgery in an asleep-awake-asleep setting. Strip electrode placement was guided by classical Penfield stimulation of positive language sites and fiber tracking of the arcuate fascicle. CCEPs were elicited with alternating monophasic single pulses of 1.1 Hz frequency and recorded as averaged signals. Intraoperatively, there was no post-processing of the signal., Results: Ninety-seven CCEPs from 19 patients were analyzed. There was no significant difference in CCEP properties when comparing awake versus asleep, nor BtW versus WtB. CCEP amplitude and latency were affected by tumor location and histopathology. CCEP features after tumor resection correlated with short- and long-term postoperative aphasia., Conclusion: CCEP recordings are feasible during minimally invasive surgery. CCEPs might be surrogate markers for altered connectivity of the language tracts., Significance: This study may guide the incorporation of CCEPs into intraoperative neurophysiological monitoring., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

We explored the functional outcome following awake surgery and Real-Time Neuropsychological Testing (RTNT) in the left insula. We carried out a longitudinal investigation by comparing the patients' language profile, and, in particular, the object-naming skills and the associated fMRI network, of pre-surgery and follow-up (i.e., a few months after surgery) in a group of 23 patients harboring a left-sided low grade glioma centered to the insulo-temporal area. Tumor resection, performed while continuously monitoring patients' performance by RNTN, was high (median = 92 %). From the neuropsychological viewpoint, almost all patients displayed preserved naming and language skills in general, both before surgery and at follow-up, when they recovered from a transient impairment recorded immediately after surgery. From the functional imaging viewpoint, the naming networks of the two assessment times were almost equivalent, with non-parametric analyses showing brain remodeling involving perilesional areas preoperatively and the contralesional, healthy, insula at follow-up. We discussed the anatomo-functional mechanisms that contributed to the preservation of the functional and cognitive pattern as observed in this longitudinal study, with a particular focus on the promising plasticity potential of the left insular area. In particular, we commented that, at least in our patient series and by applying an optimized surgical procedure, surgery in the insula was safe and generally contributed to the preservation of the language functions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Glioma is the most common primary malignant brain tumor in adults and remains an incurable disease at present. Thus, there is an urgent need for progress in finding novel molecular mechanisms that control the progression of glioma which could be used as therapeutic targets for glioma patients. The RNA binding protein cytoplasmic polyadenylate element-binding protein 2 (CPEB2) is involved in the pathogenesis of several tumors. However, the role of CPEB2 in glioma progression is unknown. In this study, the functional characterization of the role and molecular mechanism of CPEB2 in glioma were examined using a series of biological and cellular approaches in vitro and in vivo. Our work shows CPEB2 is significantly downregulated in various glioma patient cohorts. Functional characterization of CPEB2 by overexpression and knockdown revealed that it inhibits glioma cell proliferation and promotes apoptosis. CPEB2 exerts an anti-tumor effect by increasing p21 mRNA stability and inducing G1 cell cycle arrest in glioma. Overall, this work stands as the first report of CPEB2 downregulation and involvement in glioma pathogenesis, and identifies CPEB2 as an important tumor suppressor gene through targeting p21 in glioma, which revealed that CPEB2 may become a promising predictive biomarker for prognosis in glioma patients., (© 2024. The Author(s).)

Gliomas are the most prevalent primary tumor of the central nervous system. Despite advances in imaging technologies, neurosurgical techniques, and radiotherapy, a cure for high-grade glioma remains elusive. Several groups have reported that protein tyrosine phosphatase receptor type Z (PTPRZ) is highly expressed in glioblastoma, and that targeting PTPRZ attenuates tumor growth in mice. PTPRZ is modified with diverse glycan, including the PTPRZ-unique human natural killer-1 capped O-mannosyl core M2 glycans. However, the regulation and function of these unique glycans are unclear. Using CRISPR genome-editing technology, we first demonstrated that disruption of the PTPRZ gene in human glioma LN-229 cells resulted in profoundly reduced tumor growth in xenografted mice, confirming the potential of PTPRZ as a therapeutic target for glioma. Furthermore, multiple glycan analyses revealed that PTPRZ derived from glioma patients and from xenografted glioma expressed abundant levels of human natural killer-1-capped O-Man glycans via extrinsic signals. Finally, since deficiency of O-Man core M2 branching enzyme N-acetylglucosaminyltransferase IX (GnT-IX) was reported to reduce PTPRZ protein levels, we disrupted the GnT-IX gene in LN-229 cells and found a significant reduction of glioma growth both in vitro and in the xenograft model. These results suggest that the PTPR glycosylation enzyme GnT-IX may represent a promising therapeutic target for glioma., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers 1,2 . Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity 3-8 ; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: PVT1, a previously uncharacterized lncRNA, was identified as a critical regulator involved in multiple functions in tumor, including cell proliferation, cell motility, angiogenesis and so on. However, the clinical significance and underlying mechanism of PVT1 was not be fully explored in glioma., Methods: In this study, 1210 glioma samples with transcriptome data from three independent databases (CGGA RNA-seq, TCGA RNA-seq and GSE16011 cohorts) were enrolled in this study. Clinical information and genomic profiles containing somatic mutations and DNA copy numbers were collected from TCGA cohort. The R software was performed for statistical calculations and graphics. Furthermore, we validated the function of PVT1 in vitro., Results: The results indicated that higher PVT1 expression was associated with aggressive progression of glioma. Cases with higher PVT1 expression always accompanied by PTEN and EGFR alteration. In addition, functional analyses and western blot results suggested that PVT1 inhibited the sensitivity of TMZ chemotherapy via JAK/STAT signaling. Meanwhile, knockdown of PVT1 increased the sensitivity of TZM chemotherapy in vitro. Finally, high PVT1 expression was associated with reduced survival time and may serve as a strong prognostic indicator for gliomas., Conclusions: This study demonstrated that PVT1 expression strongly correlated with tumor progression and chemo-resistance. PVT1 may become a potential biomarker for the diagnosis and treatment in glioma., (© 2023. The Author(s).)

Spinal dural arteriovenous fistulae (SDAVF) are most commonly idiopathic in origin but may occasionally be seen secondary to surgery, trauma, or inflammation. We report a case of 27-year-old male who came with features of a myelopathy. He was found to have an SDAVF associated with leptomeningeal spread (LMS) of a previously treated high-grade cerebral glioma. Hemorrhagic presentation of gliomas, as in this case, is due to upregulation of vascular endothelial growth factor, which has also been postulated to play a role in the development of SDAVFs. This may suggest a possible mechanism of induction of secondary SDAVFs associated with such tumors. While the coexistence of intracranial neoplasms with vascular malformations has been reported previously, this is the first case report of LMS of a high-grade glioma associated with an SDAVF., Competing Interests: None

Objective: To report our experience and investigate frequencies of adverse events and functional status from the first 5 years of performing awake surgery for gliomas in a single-center population-based setting., Methods: We conducted a review of all patients with a glioma treated with awake surgery during the first 5 years following introduction of awake surgery at our center (February 2015 to February 2020). We assessed functional and radiological outcome, with adverse events classified according to the Landriel-Ibanez classification for neurosurgical complications, while neurological deficits were further subdivided into transient vs permanent. We sought to analyze our initial results and learning curve, as well as compare our results with literature., Results: Forty-two patients were included. The median age was 38 years (range 18-66) and 13 (31%) were female. The indication for awake surgery was a presumed glioma in or near an eloquent area. The overall 30-day complication rate was 25 (59%), with 19 (45%) grade I complications, 3 (7%) grade II complications, and 3 (7%) grade III complications. Fifteen patients (36%) experienced transient neurological deficits, and 11 (26%) permanent neurological deficits. At 3-month follow-up, the Karnofsky Performance Score was 80 or higher for the entire cohort. The median extent of resection was 87%, with GTR achieved in 11 (26%). In search of potential learning curve difficulties, patients were divided into the 21 patients treated first (Early Group) versus the remaining 21 patients treated later (Late Group); no statistically significant difference in operating time, amount of tumor removed, or incidence of long-term postoperative neurological deficit was identified between groups. No awake surgery was aborted due to seizures. Comparison to the literature was limited by the diverse and unsystematic way in which previous studies have reported adverse events after awake craniotomy for gliomas., Conclusion: We provide a standardized report of adverse events and functional status following awake surgery for glioma during a single-center 5-year learning period, with similar rates of severe adverse events and functional outcome compared to literature without concerns of substantial learning curve difficulties. However, this comparison was flawed by non-standardized reporting of complications, highlighting a demand for more standardized reporting of adverse events after awake craniotomies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

The balance between ubiquitination and deubiquitination is crucial for protein stability, function and location under physiological conditions. Dysregulation of E1/E2/E3 ligases or deubiquitinases (DUBs) results in malfunction of the ubiquitin system and is involved in many diseases. Increasing reports have indicated that ubiquitin-specific peptidases (USPs) play a part in the progression of many kinds of cancers and could be good targets for anticancer treatment. Glioma is the most common malignant tumor in the central nervous system. Clinical treatment for high-grade glioma is unsatisfactory thus far. Multiple USPs are dysregulated in glioma and have the potential to be therapeutic targets. In this review, we collected studies on the roles of USPs in glioma progression and summarized the mechanisms of USPs in glioma tumorigenesis, malignancy and chemoradiotherapy resistance., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To evaluate the feasibility of intravoxel incoherent motion (IVIM) in assessing blood-brain barrier (BBB) integrity and microvasculature in tumoral tissue of glioma patients., Methods: Images from 8 high-grade and 4 low-grade glioma patients were acquired on a 3 T MRI scanner. Acquisition protocol included pre- and post-contrast T1- and T2-weighted imaging, FLAIR, dynamic susceptibility contrast (DSC), and susceptibility-weighted imaging (SWI). In addition, IVIM was acquired with 15 b-values and fitted under the non-negative least square (NNLS) model to output the diffusion (D) and pseudo-diffusion (D*) coefficients, perfusion fraction (f), and f times D* (fD*) maps., Results: IVIM perfusion-related maps were sensitive to (1) blood flow and perfusion alterations within the microvasculature of brain tumors, in agreement with intra-tumoral susceptibility signal (ITSS); (2) enhancing areas of BBB breakdown in agreement with DSC maps as well as areas of BBB abnormality that was not detected on DSC maps; (3) enhancing perfusion changes within edemas; (4) detecting early foci of increased perfusion within low-grade gliomas., Conclusion: The results suggest IVIM may be a promising approach to delineate tumor extension and progression in size, and to predict histological grade, which are clinically relevant information that characterize tumors and guide therapeutic decisions in patients with glioma., (© 2021. The Author(s), under exclusive licence to European Society for Magnetic Resonance in Medicine and Biology (ESMRMB).)

Historically, the study of patients with spatial neglect has provided fundamental insights into the neural basis of spatial attention. However, lesion mapping studies have been unsuccessful in establishing the potential role of associative networks spreading on the dorsal-medial axis, mainly because they are uncommonly targeted by vascular injuries. Here we combine machine learning-based lesion-symptom mapping, disconnection analyses and the longitudinal behavioral data of 128 patients with well-delineated surgical resections. The analyses show that surgical resections in a location compatible with both the supplementary and the cingulate eye fields, and disrupting the dorsal-medial fiber network, are specifically associated with severely diminished performance on a visual search task (i.e., visuo-motor exploratory neglect) with intact performance on a task probing the perceptual component of neglect. This general finding provides causal evidence for a role of the frontal-medial network in the voluntary deployment of visuo-spatial attention., (© 2022. The Author(s).)

Purpose: Impaired neurocognitive function (NCF) is extremely common in patients with higher grade primary brain tumor. We previously reported evidence of genetic variants associated with NCF in glioma patients prior to treatment. However, little is known about the effect of genetic variants on NCF decline after adjuvant therapy., Methods: Patients (N = 102) completed longitudinal NCF assessments that included measures of verbal memory, processing speed, and executive function. Testing was conducted in the postoperative period with an average follow up interval of 1.3 years. We examined polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase)., Results: Five polymorphisms were associated with longitudinal changes in processing speed and 14 polymorphisms with executive function. Change in processing speed was strongly associated with MCPH1 rs17631450 (P = 2.2 × 10 -7 ) and CCDC26 rs7005206 (P = 9.3 × 10 -7 ) in the telomerase pathway; while change in executive function was more strongly associated with FANCF rs1514084 (P = 2.9 × 10 -6 ) in the DNA repair pathway and DAOA rs12428572 (P = 2.4 × 10 -5 ) in the cognitive pathway. Joint effect analysis found significant genetic-dosage effects for longitudinal changes in processing speed (P trend  = 1.5 × 10 -10 ) and executive function (P trend  = 2.1 × 10 -11 ). In multivariable analyses, predictors of NCF decline included progressive disease, lower baseline NCF performance, and more at-risk genetic variants, after adjusting for age, sex, education, tumor location, histology, and disease progression., Conclusion: Our longitudinal analyses revealed that polymorphisms in telomerase, DNA repair, and cognitive pathways are independent predictors of decline in NCF in glioma patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intramedullary spinal cord tumors are a rare and understudied cancer with poor treatment options and prognosis. Our prior study used a combination of PDGF-B, HRAS, and p53 knockdown to induce the development of high-grade glioma in the spinal cords of minipigs. In this study, we evaluate the ability of each vector alone and combinations of vectors to produce high-grade spinal cord gliomas. Eight groups of rats ( n = 8/group) underwent thoracolumbar laminectomy and injection of lentiviral vector in the lateral white matter of the spinal cord. Each group received a different combination of lentiviral vectors expressing PDGF-B, a constitutively active HRAS mutant, or shRNA targeting p53, or a control vector. All animals were monitored once per week for clinical deficits for 98 days. Tissues were harvested and analyzed using hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining. Rats injected with PDGF-B+HRAS+sh-p53 (triple cocktail) exhibited statistically significant declines in all behavioral measures (Basso Beattie Bresnahan scoring, Tarlov scoring, weight, and survival rate) over time when compared to the control. Histologically, all groups except the control and those injected with sh-p53 displayed the development of tumors at the injection site, although there were differences in the rate of tumor growth and the histopathological features of the lesions between groups. Examination of immunohistochemistry revealed rats receiving triple cocktail displayed the largest and most significant increase in the Ki67 proliferation index and GFAP positivity than any other group. PDGF-B+HRAS also displayed a significant increase in the Ki67 proliferation index. Rats receiving PDGF-B alone and PDGF-B+ sh-p53 displayed more a significant increase in SOX2-positive staining than in any other group. We found that different vector combinations produced differing high-grade glioma models in rodents. The combination of all three vectors produced a model of high-grade glioma more efficiently and aggressively with respect to behavioral, physiological, and histological characteristics than the rest of the vector combinations. Thus, the present rat model of spinal cord glioma may potentially be used to evaluate therapeutic strategies in the future.

Recent developments in the biology of malignant gliomas have demonstrated that glioma cells interact with neurons through both paracrine signaling and electrochemical synapses. Glioma-neuron interactions consequently modulate the excitability of local neuronal circuits, and it is unclear the extent to which glioma-infiltrated cortex can meaningfully participate in neural computations. For example, gliomas may result in a local disorganization of activity that impedes the transient synchronization of neural oscillations. Alternatively, glioma-infiltrated cortex may retain the ability to engage in synchronized activity in a manner similar to normal-appearing cortex but exhibit other altered spatiotemporal patterns of activity with subsequent impact on cognitive processing. Here, we use subdural electrocorticography to sample both normal-appearing and glioma-infiltrated cortex during speech. We find that glioma-infiltrated cortex engages in synchronous activity during task performance in a manner similar to normal-appearing cortex but recruits a diffuse spatial network. On a temporal scale, we show that signals from glioma-infiltrated cortex have decreased entropy, which may affect its ability to encode information during nuanced tasks such as production of monosyllabic versus polysyllabic words. Furthermore, we show that temporal decoding strategies for distinguishing monosyllabic from polysyllabic words were feasible for signals arising from normal-appearing cortex but not from glioma-infiltrated cortex. These findings inform our understanding of cognitive processing in chronic disease states and have implications for neuromodulation and prosthetics in patients with malignant gliomas., Competing Interests: The authors declare no competing interest.

Gliomas are the most common malignant brain tumors in adults, characterized by a high proliferation and invasion. The tumor microenvironment is rich in growth-promoting signals and immunomodulatory pathways, which increase the tumor's aggressiveness. In response to hypoxia and glioma therapy, the amounts of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) strongly increase in the extracellular space, and the purinergic signaling is triggered by nucleotides' interaction in P2 receptors. Several cell types are present in the tumor microenvironment and can facilitate tumor growth. In fact, tumor cells can activate platelets by the ADP-P2Y 12 engagement, which plays an essential role in the cancer context, protecting tumors from the immune attack and providing molecules that contribute to the growth and maintenance of a rich environment to sustain the protumor cycle. Besides platelets, the P2Y 12 receptor is expressed by some tumors, such as renal carcinoma, colon carcinoma, and gliomas, being related to tumor progression. In this context, this review aims to depict the glioma microenvironment, focusing on the relationship between platelets and tumor malignancy.

A biphasic computational model of a growing, vascularized glioma within brain tissue was developed to account for unique features of gliomas, including soft surrounding brain tissue, their low stiffness relative to brain tissue, and a lack of draining lymphatics. This model is the first to couple nonlinear tissue deformation with porosity and tissue hydraulic conductivity to study the mechanical interaction of leaky vasculature and solid growth in an embedded glioma. The present model showed that leaky vasculature and elevated interstitial fluid pressure produce tensile stress within the tumor in opposition to the compressive stress produced by tumor growth. This tensile effect was more pronounced in softer tissue and resulted in a compressive stress concentration at the tumor rim that increased when tumor was softer than host. Aside from generating solid stress, fluid pressure-driven tissue deformation decreased the effective stiffness of the tumor while growth increased it, potentially leading to elevated stiffness in the tumor rim. A novel prediction of reduced porosity at the tumor rim was corroborated by direct comparison with estimates from our in vivo imaging studies. Antiangiogenic and radiation therapy were simulated by varying vascular leakiness and tissue hydraulic conductivity. These led to greater solid compression and interstitial pressure in the tumor, respectively, the former of which may promote tumor infiltration of the host. Our findings suggest that vascular leakiness has an important influence on in vivo solid stress, stiffness, and porosity fields in gliomas given their unique mechanical microenvironment., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Non-invasively measured brain activity is related to progression-free survival in glioma patients, suggesting its potential as a marker of glioma progression. We therefore assessed the relationship between brain activity and increasing tumor volumes on routine clinical magnetic resonance imaging (MRI) in glioma patients. Postoperative magnetoencephalography (MEG) was recorded in 45 diffuse glioma patients. Brain activity was estimated using three measures (absolute broadband power, offset and slope) calculated at three spatial levels: global average, averaged across the peritumoral areas, and averaged across the homologues of these peritumoral areas in the contralateral hemisphere. Tumors were segmented on MRI. Changes in tumor volume between the two scans surrounding the MEG were calculated and correlated with brain activity. Brain activity was compared between patient groups classified into having increasing or stable tumor volume. Results show that brain activity was significantly increased in the tumor hemisphere in general, and in peritumoral regions specifically. However, none of the measures and spatial levels of brain activity correlated with changes in tumor volume, nor did they differ between patients with increasing versus stable tumor volumes. Longitudinal studies in more homogeneous subgroups of glioma patients are necessary to further explore the clinical potential of non-invasively measured brain activity., (© 2021. The Author(s).)

Purpose: LHX9 methylation has been reported in many tumors, but its functions and related mechanisms in glioma are still unknown and need to be verified., Methods: The protein level of LHX9 in glioma tissues was examined using western blotting and immunohistochemistry, and the functions of LHX9 in glioma cell lines were investigated using MTT and colony formation assays. In addition, the interaction between LHX9 and P53 was analyzed by immunoprecipitation, and the roles of LHX9 in cancer metabolism were explored by measuring metabolites., Results: In this study, we found that the LHX9 expression level was decreased in glioma specimens, and the upregulation of LHX9 expression inhibited the growth of glioma cells in liquid medium and on soft agar. Regarding the molecular mechanism, we found that LHX9 interacted with p53, and downregulation of LHX9 promoted the expression of the glycolysis-related enzyme PGK1 and increased the lactic acid content. By interfering with the expression of LHX9, the tumorigenicity of glioma cells was promoted, an outcome blocked by further interference with PGK1 expression., Conclusion: In summary, the decreased expression of LHX9 in gliomas activates the expression of the glycolysis-related enzyme PGK1, thereby promoting the development of gliomas, suggesting that the LHX9-PGK1 signaling axis can be used as a target for the treatment of glioma.

Pharmacological treatment of gliomas and other brain-infiltrating tumors remains challenging due to limited delivery of most therapeutics across the blood-brain barrier (BBB). Transcranial MRI-guided focused ultrasound (FUS), an emerging technology for noninvasive brain treatments, enables transient opening of the BBB through acoustic activation of circulating microbubbles. Here, we evaluate the safety and utility of transcranial microbubble-enhanced FUS (MB-FUS) for spatially targeted BBB opening in patients with infiltrating gliomas. In this Phase 0 clinical trial (NCT03322813), we conducted comparative and quantitative analyses of FUS exposures (sonications) and their effects on gliomas using MRI, histopathology, microbubble acoustic emissions (harmonic dose [HD]), and fluorescence-guided surgery metrics. Contrast-enhanced MRI and histopathology indicated safe and reproducible BBB opening in all patients. These observations occurred using a power cycling closed feedback loop controller, with the power varying by nearly an order of magnitude on average. This range underscores the need for monitoring and titrating the exposure on a patient-by-patient basis. We found a positive correlation between microbubble acoustic emissions (HD) and MR-evident BBB opening ( P = 0.07) and associated interstitial changes ( P < 0.01), demonstrating the unique capability to titrate the MB-FUS effects in gliomas. Importantly, we identified a 2.2-fold increase of fluorescein accumulation in MB-FUS-treated compared to untreated nonenhancing tumor tissues ( P < 0.01) while accounting for vascular density. Collectively, this study demonstrates the capabilities of MB-FUS for safe, localized, controlled BBB opening and highlights the potential of this technology to improve the surgical and pharmacologic treatment of brain tumors., Competing Interests: The authors declare no competing interest.